Novel biotin-functionalized lipidic nanocarriers for encapsulating BpT and Bp4eT iron chelators: evaluation of potential anti-tumour efficacy by in vitro, in vivo and pharmacokinetic studies in A549 mice models

Abstract

Tumour cells have a high demand for iron (Fe) due to their rapid rate of proliferation. Strategies to target intracellular iron for antitumour therapy have not been systematically explored. The benzoylpyridine thiosemicarbazone (BpT) group of Fe-binding drugs represent a promising class of anti-tumour agents; however, their low aqueous solubility and high protein binding limit their clinical efficacy. In this work, we have explored the possibility of using solid lipid nanoparticles (SLNs) to develop a nanocarrier system that can deliver a drug cargo of BpT drugs to tumour sites. Herein, we prepared targeted biotinylated stearic acid based PEGylated SLN formulations for entrapment of benzoylpyridine thiosemicarbazone (BpT) and its analogue 4-ethyl benzoylpyridine thiosemicarbazone (Bp4eT) by the ultrasonication method, resulting in BpT-PB-SLNs and Bp4eT-PB-SLNs (size 115 to 120 nm, zeta potential −28 to −36 mV) with EEs of 72%. These formulations had negligible hemolytic activity and sustained drug release for 7 days. Radiolabeling with technetium-99m (^99mTc) radionuclide facilitated the evaluation of their biological parameters both ex vivo and in vivo. Their blood kinetics profile showed prolonged systemic circulation compared to native drugs (BpT and Bp4eT) in New Zealand albino rabbits. The biodistribution studies performed in A-549 xenografted athymic mice depicted higher tumour uptake and lower non-specific uptake than native drugs as confirmed through whole body SPECT imaging by semi-quantitative analysis. This research presents for the first time a novel lipidic nanocarrier system in the form of biotin functionalised PEGylated SLNs that can help deliver iron chelators in a highly sustained manner and therefore hold potential to enhance their intracellular uptake and hence their antitumour efficacy.